ABSTRACT Although significant progress has been made in neonatal intensive care units, preterm infants continue to suffer from significant morbidities and comorbidities such as hypoxia-ischemia, intraventricular hemorrhage, and white matter injury/periventricular leukomalacia. For example, 65-85% of extreme preterm infants (? 28 weeks of gestational age) have patent ductus arteriosus (PDA) at first week of life, which leads to shunting of blood between the systemic and the pulmonary circulations. Because of many complications associated with PDA, the majority of extreme preterm infants receive medical or surgical therapy in an attempt to close the PDA. However, PDA and associated treatment procedures may cause large perturbations in cerebral hemodynamics and metabolism, thus impacting neonatal brain health. Currently, there is no clinically accepted quantitative monitor for continuous bedside assessment of neonatal brain health. We propose to develop and test a near-infrared diffuse speckle contrast flow-oximeter (DSCFO), which will enable simultaneous quantification of cerebral blood flow (CBF), cerebral blood oxygen saturation (StO2), and cerebral metabolic rate of tissue oxygen consumption (CMRO2) in infants' brains. The DSCFO uses two small laser diodes at different wavelengths (690 nm and 830 nm) and a tiny bare complementary metal-oxide semiconductor (CMOS) sensor chip with no lenses to rapidly quantify spatial diffuse speckle fluctuations resulting from moving red blood cells for CBF measurements in relatively deep tissues (up to 8 mm). Alternative measurements of light intensity changes at the two wavelengths will enable quantification of StO2 variations. Knowing CBF and StO2 together will allow for the derivation of CMRO2. Compared to conventional near-infrared diffuse optical technologies, DSCFO is an innovative design with significantly lower cost (<$2500), a faster sampling rate (milliseconds), more detection channels on the high- resolution CMOS pixel array, and a smaller probe (25 mm x 15 mm), which is particularly applicable to cerebral monitoring in the small heads of newborn infants. In Specific Aim 1, the proposed DSCFO device will be constructed and calibrated in head-simulating tissue phantoms and adults' forearms against other established standards. In Specific Aim 2, the calibrated DSCFO device will be further examined in clinic to measure CBF, StO2, and CMRO2 in preterm infants with PDA undergoing indomethacin treatment. We hypothesize that neonatal cerebral hemodynamics/metabolism altered by the PDA and treatment can be detected by the DSCFO, which should reasonably correlate with other physiological measures and clinical outcomes. The measurement of multiple cerebral hemodynamic/metabolic variables together (i.e., CBF, StO2, and CMRO2) is expected to provide better assessment of neonatal brain health than a single parameter alone, which may help optimize patient care and reduce adverse cerebral impacts. Furthermore, the DSCFO has the potential to be used for cerebral diagnosis and therapeutic monitoring of many other diseases in infants (e.g., hypoxic/ischemic injury, shock/hypotension, intermittent hypoxemia).